1. Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Treatment of Chronic HCV Genotype 2 Robert G. Gish MD Consultant/Staff Physician, Stanford University Medical Center Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona Clinical Professor (Adjunct) of Medicine, University of Nevada, Las Vegas Medical Director, Hepatitis B Foundation Vice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR) Last Updated: October 4, 2015

2. Hepatitis web study Hepatitis web study Background and Definitions Initial Treatment Retreatment of Patients with Prior Treatment Failure Disappearance of Issues and Controversies Is There a Need for Future Therapies? Summary Background and Definitions Initial Treatment Retreatment of Patients with Prior Treatment Failure Disappearance of Issues and Controversies Is There a Need for Future Therapies? Summary Treatment of Chronic HCV Genotype 2

3. Hepatitis web study Hepatitis web study Background and Definitions T REATMENT OF C HRONIC H EPATITIS C: G ENOTYPE 2

4. Hepatitis web study Treatment of Chronic HCV Genotype 2 Background Genotype 2 is second most common HCV genotype in US Up to 85% of patients have contraindications for interferon therapy Small proportion of untreated patients are genotype 2 today due to historically high treatment and cure rates

5. Hepatitis web study Virologic Responses with HCV Therapy Sustained Virologic Response at 12 Weeks Post Therapy (SVR12) Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment Undetectable Treatment Post Treatment 12 Weeks End of Treatment SVR12

6. Hepatitis web study Hepatitis web study Initial Treatment T REATMENT OF C HRONIC H EPATITIS C: G ENOTYPE 2

7. Hepatitis web study Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).www.hcvguidelines.org AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations Initial Treatment of Patients with Genotype 2 Chronic HCV Genotype 2 HCV: Initial Treatment Recommended Regimen, Patients without Cirrhosis Sofosbuvir + Ribavirin x 12 weeks Recommended Regimen, Patients with Cirrhosis Sofosbuvir + Ribavirin x 16 weeks Recommended Regimen, Patients Not Able to Tolerate Ribavirin Daclatasvir + Sofosbuvir x 12 weeks (consider 24 weeks with cirrhosis)

8. Hepatitis web study Treatment-Naïve with Genotype 2 Chronic HCV Key Studies Sofosbuvir + Ribavirin - FISSION - POSITRON - VALENCE Daclatasvir + Sofosbuvir - A144040 - ALLY-2

9. Hepatitis web study Hepatitis web study Initial Therapy: Genotype 2 Sofosbuvir plus Ribavirin

10. Hepatitis web study Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87. 2436 Week 012 N =243 N =256 SVR12 Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3 FISSION Trial: Design Peginterferon + RBV (fixed-dose) Sofosbuvir + RBV (weight-based) Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Weight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Fixed-dose Ribavirin (in 2 divided doses): 800 mg/day

11. Hepatitis web study Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3 FISSION Trial: Results SVR12 by Genotype Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87. RBV = Ribavirin; PEG = Peginterferon 68/7052/67102/183110/176170/253162/243

12. Hepatitis web study Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77. N =71 Placebo 12 weeks Sofosbuvir + RBV 12 weeks Sofosbuvir + RBV 12 weeks N =207 SVR12 Sofosbuvir + Ribavirin for HCV GT 2 or 3 (PEG-IFN not an option) POSITRON Trial: Design 24 Week 012 SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

13. Hepatitis web study Sofosbuvir + Ribavirin for HCV GT 2,3 (PEG not an option) POSITRON: Results with Sofosbuvir + Ribavirin SVR12 by HCV Genotype Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77. Placebo arm = 0% SVR12 101/10960/98

14. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014 2436 Week 012 Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Treatment Arms SVR12 Sofosbuvir + RBV (n = 73) SVR12 Sofosbuvir + RBV (n = 250) GT 2 GT 3 Drug Dosing Sofosbuvir 400 mg once daily Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Note: 85 patients enrolled in placebo arm

15. Hepatitis web study Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment-Naïve GT 2 SVR12 for Treatment-Naïve GT 2 Source: Zeuzem S, et al. N Engl J Med. 2014

16. Hepatitis web study Hepatitis web study Initial Therapy: Genotype 2 Daclatasvir plus Sofosbuvir

17. Hepatitis web study Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21. Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3 A1444040 Design: Treatment-Naïve 24 Week Rx (Part 1) SOF × 7 days, then DCV + SOF SVR12 N =14 Drug Dosing Daclatasvir (DCV): 60 mg once daily Sofosbuvir (SOF): 400 mg once daily Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg) Ribavirin (RBV): GT 2,3 (800 mg/day) Rx Naïve GT 2 or 3 n = 44 n = 14 n = 16 DCV + SOF n = 14 DCV + SOF + RBV SVR12 SOF × 7 days, then DCV + SOF SVR12 Rx Naïve GT 1a/1b n = 44 n = 14 n = 15 DCV + SOF n = 15 DCV + SOF + RBV SVR12 Week 0241236

18. Hepatitis web study Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21. Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3 Treatment-Naïve 24 Week Rx: Results (Part 1) DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin 14/1614/1412/14

19. Hepatitis web study Source: Wyles DL, et al. N Engl J Med. 2015;373:714-25. Treatment-Experienced N = 52 Treatment-Naïve N = 101 SVR12 Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection ALLY-2 Trial: Design Daclatasvir + Sofosbuvir Drug Dosing Daclatasvir: 60 mg once daily; with efavirenz and nevirapine the dose was increased to 90 mg once daily and with ritonavir-boosted protease inhibitors the dose was decreased to 30 mg once daily Sofosbuvir: 400 mg once daily Week 02412 Treatment-Naïve N = 50 SVR12 Daclatasvir + Sofosbuvir SVR12 820

20. Hepatitis web study Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection ALLY-2 Trial: Results for Genotype 2 SVR12, Genotype 2 Source: Wyles DL, et al. N Engl J Med. 2015;373:714-25. Abbreviations: DCV = daclatasvir; SOF = sofosbuvir 11/11 5/62/2

21. Hepatitis web study Hepatitis web study Retreatment of Persons in Whom Prior Therapy Failed T REATMENT OF C HRONIC H EPATITIS C: G ENOTYPE 2

22. Hepatitis web study Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).www.hcvguidelines.org AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations GT2 HCV: Retreatment of Prior Failure with PR Genotype 2 HCV: Retreatment, Prior Failure with Peginterferon + Ribavirin Recommended Regimen Sofosbuvir + Ribavirin x 16 or 24 weeks* Alternative Regimen Sofosbuvir + Ribavirin + Peginterferon x 12 weeks (if patient interferon eligible) *The decision to use 16 or 24 weeks should be made on an individual patient basis

23. Hepatitis web study Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).www.hcvguidelines.org AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations GT 2 HCV: Retreatment of Prior Failure with SOF + RBV Genotype 2 HCV: Retreatment, Prior Failure with Sofosbuvir + Ribavirin Recommended Regimen for Patients NOT Eligible to Receive Interferon Daclatasvir + Sofosbuvir +/- Ribavirin x 24 weeks Recommended Regimen for Patients Eligible to Receive Interferon Sofosbuvir + Ribavirin + Peginterferon x 12 weeks

24. Hepatitis web study Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).www.hcvguidelines.org AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations Criteria for Interferon Ineligible NOT Eligible to Receive Interferon Defined as one or more of the following: Intolerance to interferon Autoimmune hepatitis and other autoimmune disorders Hypersensitivity to peginterferon or any of its components Decompensated hepatic disease Major uncontrolled depressive illness A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL A history of preexisting cardiac disease

25. Hepatitis web study Retreatment of Genotype 2 Chronic HCV Key Studies Prior Failure with Peginterferon + Ribavirin - FUSION - VALENCE - LONESTAR-2 - BOSON Prior Failure with Sofosbuvir + Ribavirin - Retreatment of prior Sofosbuvir Failure

26. Hepatitis web study Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77. N =98 Sofosbuvir + RBV 16 weeks Sofosbuvir + RBV 16 weeks Sofosbuvir + RBV 12 weeks Sofosbuvir + RBV 12 weeks N =103 SVR12 Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3 FUSION Trial: Design 24Week0122816 SVR12 Placebo Drug Dosing Sofosbuvir: 400 mg once daily Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

27. Hepatitis web study Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3 FUSION Trial: Results for GT2 SVR12 for Treatment-Experienced GT2 Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77. SOF = Sofosbuvir; RBV = Ribavirin 31/3630/3225/266/1023/237/9

28. Hepatitis web study Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001. 2436 Week 012 Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Treatment Arms SVR12 Sofosbuvir + RBV (n = 73) SVR12 Sofosbuvir + RBV (n = 250) GT 2 GT 3 Drug Dosing Sofosbuvir 400 mg once daily Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment Note: 85 patients enrolled in placebo arm

29. Hepatitis web study Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 Treatment Experienced GT2 : 12 weeks of treatment SVR12 for Treatment-Experienced GT 2 Source: Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

30. Hepatitis web study Source: Lawitz E, et al. Hepatology. 2015:61:769-75. Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3 LONESTAR-2 Trial: Design Sofosbuvir + Peginterferon + Ribavirin N = 47 Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg GT 2 or 3 024 Week 12 SVR12

31. Hepatitis web study Sofosbuvir + PEG + RBV for 12 weeks in Treatment-Experienced HCV GT 2 or 3 LONESTAR-2 Trial: Results SVR12 in Treatment-Experienced by HCV Genotype Source: Lawitz E, et al. Hepatology. 2015:61:769-75. 42/4722/2320/24

32. Hepatitis web study Sofosbuvir + PEG + RBV for 12 weeks in Treatment-Experienced HCV GT 2 or 3 LONESTAR-2 Trial: Results LONESTAR-2 Trial: SVR12 by Cirrhosis Status Source: Lawitz E, et al. Hepatology. 2015:61:769-75. 9/913/1410/12

33. Hepatitis web study Source: Foster GR, et al. Gastroenterololgy. 2015 Aug 3 [Epub ahead of print] Sofosbuvir + Ribavirin +/- Peginterferon for HCV GT 2 or 3 BOSON: Treatment Arms Sofosbuvir + RBV (n= 196) Sofosbuvir + RBV (n= 199) Drug Dosing Sofosbuvir 400 mg once daily Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Peginterferon alfa-2a: 180 ug/week 02436 Week 121628 SVR12 Sofosbuvir + PEG/RBV (n= 197) SVR12 Genotype 2 Prior treatment Compensated Cirrhosis Genotype 3 +/- Prior Treatment +/- Cirrhosis

34. Hepatitis web study Sofosbuvir + Ribavirin +/- Peginterferon for HCV GT 2 or 3 BOSON: Results SVR12 by Regimen and Genotype Source: Foster GR, et al. Gastroenterololgy. 2015 Aug 3 [Epub ahead of print] 13/1517/1715/16128/181153/182166/181 TE with compensated cirrhosis

35. Hepatitis web study Source: Esteban R, et al. 49 th EASL; April 2014. Abstract 08. Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3 Study Design N = 73 N = 34 Sofosbuvir + RBV Sofosbuvir + PEG + RBV Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Weight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg GT2 or GT3 02436 Week 12 SVR12

36. Hepatitis web study Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3 Preliminary Results, by Genotype SVR12 by Regimen and HCV Genotype Source: Esteban R, et al. 49 th EASL; April 2014. Abstract 08. 4/41/220/2224/3824/2625/40

37. Hepatitis web study Hepatitis web study Issues and Controversies T REATMENT OF C HRONIC H EPATITIS C: G ENOTYPE 2

38. Hepatitis web study Hepatitis C Genotype 2 Estimated Medication Costs for Treatment-Naïve & Prior Relapsers Patients with GT 2 HCV: Initial Treatment Recommended Regimen and DurationAWAC Regimen Cost Sofosbuvir + Ribavirin x 12 weeks$85,000 Sofosbuvir + Ribavirin x 16 weeks$113,000 Daclatasvir + Sofosbuvir x 12 weeks$147,000 Daclatasvir + Sofosbuvir x 24 weeks$295,000 AWAC = Average Wholesale Acquisition Cost Note: health care systems may receive substantial discounts

39. Hepatitis web study Hepatitis C Genotype 2 Estimated Medication Costs for Treatment-Naïve & Prior Relapsers Patients with GT 2 HCV: Retreatment of Patients with Prior Failure Recommended Regimen and Duration AWAC Regimen Cost Sofosbuvir + Ribavirin x 16 weeks$113,000 Sofosbuvir + Ribavirin x 24 weeks$170,000 Sofosbuvir + Ribavirin + Peginterferon x 12 weeks $97,000 Daclatasvir + Sofosbuvir +/- Ribavirin x 24 weeks$295,000 AWAC = Average Wholesale Acquisition Cost Note: health care systems may receive substantial discounts

40. Hepatitis web study Treatment of Genotype 2 Chronic HCV Issues and Controversies Cost of Therapy: what is actual discounted cost and is there a need to wait for price competition? With cure rates as high as 96%, are we over-treating most patients by treating patients for 12-24 weeks?  Can we shorten therapy to 4 or 6 weeks to save treatment costs?  Can we revitalize response guided therapy or find pretreatment predictors of SVR with short therapy? When to Defer or Decline Therapy:  Decisions on when to warehouse?  Based on mild histology or lack of evidence of systemic disease  Short lifespan  Noncompliance (Non) Role of IL-28b Testing, now obviated For treatment purposes, liver fibrosis staging primarily used to meet insurance requirements and determine HCC surveillance strategy

41. Hepatitis web study Source for Figure: Camilla Graham, MD, MPH. Beth Israel Deaconess Medical Center Data Sources: (1) Lawitz E, et al. NEJM 2013; 368:1878-87. (2) Jacobson I, et al. NEJM 2013; 368:1867-77. (3) Antiviral Drugs Advisory Committee Meeting, FDA and Gilead reviews, 10/25/2013. (4) Package Insert, Gilead.com 12/7/2013. HCV Therapy for Genotype 2 Chronic HCV Cost Analysis Based on Cost per SVR Patient CharacteristicsRegimen OptionsSVRCost per SVR Naïve, no cirrhosisSOF + RBV x 12 wks92-98%$95,263 Naïve, cirrhosisSOF + RBV x 16 wks91-94%~$154,658 Treatment experienced, no cirrhosis SOF + RBV x 12 wks91-96%$96,276 Treatment experienced, cirrhosis SOF + RBV x 16 wks78%$154,658 SOF + PEG + RBV x 12 wks93%$113,269

42. Hepatitis web study Hepatitis web study How is cost of therapy impacting treatment decisions?

43. Hepatitis web study Hepatitis web study Treatment Regimens Under Study H EPATITIS C: G ENOTYPE 2

44. Hepatitis web study Possible Future Regimens for GT-2 Unlikely  Ledipasvir-Sofosbuvir  Ombitasvir-Paritaprevir-Ritonavir Likely  ABT-493 plus ABT-450  Regimens with 5816

45. Hepatitis web study Hepatitis web study Treat now or defer therapy?

46. Hepatitis web study Factors Favoring Urgent GT2 Treatment Advanced Fibrosis (F3-F4) - Platelet count < 150,000/uL - Large spleen and/or portal vein - Esophageal varices Synthetic dysfunction, decompensated disease Systemic disease - Cryoglobulinemia ([+] Rheumatoid Factor)

47. Hepatitis web study Summary Points for Treatment of Chronic HCV GT-2 Genotype 2 highly responsive to 12 weeks of all-oral therapy Relatively little retreatment data since high SVR rates with therapy in naïve patients Few GT2 studies moving forward with new therapies Will be difficult to enroll large studies required for licensing trials New pangenotypic drugs will be used for genotype 2 off-label (prediction)

48. Hepatitis web study Hepatitis web study This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online www.hepatitisc.uw.edu www.hepatitisc.uw.edu Hepatitis Web Study http://depts.washington.edu/hepstudy/ http://depts.washington.edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention. This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects. Hepatitis C Online www.hepatitisc.uw.edu www.hepatitisc.uw.edu Hepatitis Web Study http://depts.washington.edu/hepstudy/ http://depts.washington.edu/hepstudy/ Funded by a grant from the Centers for Disease Control and Prevention.